Alzheimer's disease (AD) may be triggered by a series of microvascular ischemic events in the brain, notably in the medial temporal lobe. These events lead to localized hypoxia and perhaps hypoglycemia which in turn lead to the formation of neurofibrillary tangles in vulnerable neurons of the hippocampal formation. The deposition of these tangles leads eventually to death of the neurons and thus the loss of synaptic connections between neurons within the medial temporal lobe and between neurons of the medial temporal lobe and neurons in the neocortex. It is the loss of these neuronal connections that leads to the symptoms of AD.
The above is supported by the following.
In addition to the well-known amyloid angiopathy, small blood vessels in the brain in AD show several abnormalities that could lead to a decrease in blood flow, notably a reduced density, reduced diameter, a disorganized angioarchitecture ((1) de la Torre and Mussivand, 1993; (2) Kalaria, 1992), and a loss of endothelium ((3) Kalaria and Hedera, 1995), which are particularly prominent in the hippocampus ((4) Fischer et al, 1990).
It is notable that the microvascular abnormalities found in the hippocampus in AD are especially prominent in area CA1 ((5) Buee et al, 1994), since the same area of the hippocampus is especially vulnerable to hypoxia ((6) Schmidt-Kastner and Freund, 1991) and is the part of the hippocampus that shows the greatest density of neurofibrillary tangles ((7) Ball et al, 1985), and the greatest cell loss ((8) West et al, 1994) in AD.
It is believed that one of the causes of the microvascular events leading to ischemia in the medial temporal lobe is a moderate deficiency in folate and vitamin B.sub.12 which, in turn, lead to an elevation of plasma total homocysteine levels. It is the toxic effect of homocysteine on the blood vessels that initiates the pathological cascade process leading to changes in the microvasculature.
Thus, the microvascular abnormalities found in AD could be brought about by chronic exposure to elevated levels of plasma homocysteine, which causes disorganization of the elastic lamina ((9) Rolland et al, 1995) and damage to the endothelium ((10) McCully, 1996; (11) Rose and Tudball, 1996; (12) Stamler and Slivka, 1996) in arterioles in the periphery. Small blood vessels in the brain are likely to be particularly sensitive to the toxic effect of homocysteine on the elastic fibers since cerebral vessels only have a single elastic lamina. A correlation has been found between elevated homocysteine and the risk of cerebrovascular disease such as arteriosclerotic cerebrovascular disease and stroke ((13) Brattstrom et al, 1984; (14) Brattstrom et al, 1992).
It has now been found that patients with histopathologically-confirmed Alzheimer's disease have elevated levels of serum total homocysteine. It has also been found that the raised serum level of homocysteine in Alzheimer patients is associated with reduced serum levels of two vitamins, folate and vitamin B.sub.12, that are required as co-factors in the conversion of homocysteine to methionine. It appears that the elevated homocysteine is due to a deficiency in the dietary intake or in the bioavailability of folic acid and vitamin B.sub.12.
It is also known that blood levels of homocysteine may be lowered by treatment with high doses of folate ((15) Boushey et al, 1995, (16) Stampfer and Rimm, 1996; (17) Ubbink et al, 1994).
Angiotensin-converting enzyme (ACE) inhibitors, such as captopril, fosinopril, enalapril, ceronapril, lisinopril and the like, and angiotensin II antagonists such as losartan, irbesartan, valsartan, candesartan, tasosartan and eprosartan, are known for their use as vasodilating cardiovascular agents in treating high blood pressure and congestive heart failure.
Nitrates such as isosorbide dinitrate, isosorbide mononitrate and nitroglycerin are known for their coronary and peripheral vasodilating effect in the prevention and treatment of angina pectoris. They have been shown in clinical studies to limit infarct size.